Alcohol use behaviors that begin in youth are important contributors to alcohol use disorders in adulthood. Large-scale studies of adults have identified specific genetic variants that are associated at a genome-wide level with substance use disorders. The extent to which these genetic variants, individually and with other risk factors, influence early drinking behaviors is not fully understood. The goal of this project is to determine whether genetic variants identified in adults impact the development of drinking milestones in youth and how important environmental risk factors modify these effects. We will use an existing longitudinal sample of European and African American youth collected through the Collaborative Study on the Genetics of Alcoholism (COGA). Our central hypothesis is that genetic variants will affect early alcohol- related problems and that environmental factors will modify this effect. Guided by strong preliminary data generated from analyses performed by the applicant, this hypothesis will be examined in two specific aims. Aim 1 will test the effect of wel-established targeted genetic variants on adolescent drinking behaviors from drinking initiation to DSM-5 alcohol use disorders. We will initially examine functional variants in the enzyme alcohol dehydrogenase (ADH) that have been shown to have a genome-wide significant effect on alcohol use disorders in adults. We will then examine variation in the CHRNA5-CHRNA3-CHRNAB4 nicotinic receptor subunit genes that is genome-wide significant for smoking behaviors, with growing evidence for an association with adult alcohol dependence. Aim 2 will then test how known environmental risk factors for early drinking behaviors modify the effect of these targeted genetic variants. We will focus on the two environments of peer drinking and parental monitoring, which have previously been shown to influence youth drinking patterns. The proposed research is significant because it is expected to provide insight into the complex etiology of early drinking behaviors. A better understanding of how specific genetic and environmental factors contribute to these early behaviors will add to our fundamental knowledge of the developmental processes that lead to alcohol use disorders. Ultimately, identification of modifiable risk factors that influence underlying genetic vulnerabilities has the potential to infom new interventions to reduce the burden of this severe disease.